Evidence before this study: We searched original research articles on PubMed written in English between January 1st 1980 and January 1st 2023. We assessed the quality of evidence using the GRADE approach(21). Pick’s disease is recognized as a rare frontotemporal dementia that presents with a heterogenous clinical phenotype and no therapeutic management approach is available. It is a primary 3R-tauopathy and is diagnosed post-mortem. Given the rarity of the disorder only a handful of genetic studies have been performed on individuals with Pick’s disease and an association with MAPT H1 (observed for other primary tauopathies) or H2 haplotypes was unclear. We searched PubMed using the terms: ((Pick’s disease) or (Pick disease)) and ((genetic*) or (genome wide association study) or (GWAS))

Added value of this study: Understanding the genetic etiology of the susceptibility and progression of Pick’s disease is crucial to nominate therapeutic intervention strategies. The current study established the Pick’s disease international consortium (PIC), identifying 338 pathologically defined individuals with Pick’s disease across 35 brain banks. With this unique series we were able to identify a disease risk association with the MAPT H2 haplotype, which has been nominated as protective in primary 4R tauopathies.

Implications of all the evidence available: The establishment of the PIC opens up opportunities to gain further insight into the underlying pathogenesis and etiology of Pick’s disease. Collection of these individuals will facilitate future studies not only on genetics but also provide a resource for clinicopathologic, epigenetic, transcriptomic, and proteomics studies. The observation of Pick’s disease risk association with MAPT H2 suggests that the haplotype status may influence tau 3R-4R ratio isoform expression and may inform future therapeutic strategies targeting MAPT/tau expression (e.g. antisense oligonucleotide or immunotherapy approaches).